This invention relates to blood transfusions, and more particularly relates to means and methods for autologous sequestration of blood.
As is well known by those skilled in the art, patients frequently lose blood during surgical procedures. Under circumstances in which such blood loss is excessive, blood must be replaced to avoid undue risk to the patient. Prerequisite blood transfusions are thus commonly administered prior to, during, and after surgical procedures and the like. Traditionally, blood banks have supplied various blood products to hospitals and the like according to the rules promulgated by the American Association of Blood Banks. Similarly, blood transfusion practices by physicians and in hospitals are routinely monitored by the Joint Commission on Accreditation of Healthcare Organizations.
Typically, blood products are donated by or received from family members or known or unknown individuals; such blood products are referred to as "allogeneic" products. During the 1980's, unfortunately, it was discovered that the nation's allogeneic blood supply was contaminated with the human immunodeficiency virus (HIV). This immediately heightened public awareness and caused concern among health care professionals, patients and the media related to safe administration of blood transfusions.
It will be appreciated by those skilled in the art, that in view of the dangers of HIV infection of allogeneic blood, current blood transfusion practices have become more conservative. Nevertheless, current blood testing practices are unable to prevent HIV contamination. Guidelines for administering blood transfusions have been reexamined and redefined. Safe and effective alternatives using allogeneic blood products have been explored, including synthetic blood substitutes, autotransfusion, acute normvolemic hemodilution, etc.
In an article entitled "Blood Transfusion-Induced Immunomodulation" and reviewing the immunomodulatory effects of transfusion therapy, Dennis F. Landers, Gary E. Hill, K. C. Wong and Ira J. Fox state that available data at least suggest that allogeneic blood products increase cancer recurrence after a potentially curative surgical resection. Anesth Analg, vol. 82, pp 187-204, 1996. The authors suggest a continued awareness of the risks associated with use of allogeneic blood and use of techniques which tend to reduce such risks such as lower transfusion trigger, intraoperative and postoperative readministration of shed blood, and preoperative autologous donation with or without erythropoietin.
For the use of allogeneic blood, of course, conventional blood bank practice is to collect blood from an acceptable donor in citrate to prevent coagulation. Several components are separated from the collected blood including packed red blood cells, platelets and plasma. It is also a common practice for plasma and platelets to be collected using pheresis techniques. As is well known by those skilled in the art, allogeneic whole blood is rarely used. The blood products collected at blood banks are then stored in accordance with shelf-life survivability expectations. Prior to administering allogeneic blood, the patient's blood is cross-matched to assure its compatibility with the patient's blood type.
The threshold for the actual administration of allogeneic blood by a physician anesthesiologist is presently uncertain. Prior to the current pervasive HIV-threat associated with allogeneic blood transfusions, packed red blood cell transfusions would commence when hemoglobin levels fell below 10 g/dl. But practitioners in the art currently are inclined to withhold such transfusions until hemoglobin levels fall below 6-8 g/dl, depending upon the patient's health. Obviously, an 80-year old patient having cardiovascular disease would be transfused sooner than a healthy 18-year old. See, e.g., the paper entitled "Severity of Anemia and Operative Mortality and Morbidity" by Jeffrey L. Carson, Roy M. Poses, Richard K. Spence and Gregory Bonavita published in Lancet, vol. 1, pp 727-729 in 1988. As will be appreciated by those skilled in the art, one unit of packed red blood cells typically increases the hemoglobin level by about 1 g/dl.
It is widely known that the transfusion of blood contaminated with HIV has caused thousands of cases of acquired immunodeficiency syndrome (AIDS). To reduce the risk of patients acquiring AIDS from transfused blood, allogeneic blood is routinely screened for the presence of HIV. But since the current ELISA, i.e., enzyme-linked immunosorbant assay, antibody test fails to detect donors infected with HIV during the so-called "immunologic window"--from 4 weeks to 14 months--wherein donors may be HIV-infected but test negative, the risk associated with transfusing 1 unit of allogeneic blood ranges from 1:153,000 to 1:61,000. See, M. P. Busch, at al., New England Journal of Medicine, vol. 325, pp 1-5, 1991.
Blood banks have been attempting to reduce these risks by using repeat, HIV-safe donors and by using donors designated by particular patients. But is not clear that using repeat or designated donors actually reduced the risk of HIV infection from allogeneic transfusions. Other infectious risks associated with use of allogeneic blood products include hepatitis, certain strains of gram negative bacteria which can cause septic shock, and immunosuppression which predisposes patients to increased risks of infection.
There have been several developments in the art to avoid the inherent disadvantages associated with using allogeneic blood products. For example, autologous predonation may be used by patients who donate their blood to a blood bank on a weekly basis prior to being subjected to surgery. Collection of as much as 4 units of whole blood may be scheduled as frequently as every 96 hours, provided that a patients hemoglobin must be at least 12.5 g/dl prior to each such phlebotomy. See, 21 C.F.R. .sctn. 640.3. While patients using predonation obviously have the benefit of using their own blood, there may be a problem due to "storage lesion" which develops with prolonged refrigeration of collected blood.
Another example is autotransfusion and intraoperative blood salvage, which may be used under circumstances in which extreme blood loss is anticipated. According to intraoperative blood salvage methodology, hemorrhaged blood is collected into an autotransfusion device, anticoagulated, washed and then recycled into the patient. Commonly used autotransfusion devices provide centrifugation to wash blood cells as the blood is collected. An inherent disadvantage with this method is that large amounts of citrate or heparin are mixed with the blood to avoid coagulation. As will also be understood by those skilled in the art, washed blood contains only red blood cells and is devoid of platelets or plasma. Practitioners in the art have also applied this technique postoperatively wherein blood is collected into canisters from chest tubes, and then filtered and administered back to the patient. Blood administered in this fashion is similar to serum having no fibrinogen.
As is known to those skilled in the art, heparin is commonly used during cardiac surgery to prevent coagulation of a patient's blood during cardiopulmonary bypass. Once anticoagulated, a patient's blood may be rapidly sequestered under aortic pressure. It will be understood, however, that once cardiopulmonary bypass commences, further sequestration is limited because of additional hemodilution engendered by this extra corporeal circuit. Furthermore, such a post-heparinization rapid blood sequestration procedure is apt to introduce significant risk, subjecting a patient to greater hemodynamic instability and to possible inadequate perfusion of the heart, brain, and kidneys. In the art, the apparatus used for this procedure is configured as an open circuit and fails to consider the beneficial affects of blood-warming.
Unfortunately, the impact of heparin upon blood has been observed to be fundamentally noxious to platelets. See, E. Saltzman, et al., "Thromboresistance of Heparin-Coated Surfaces," Chemistry and Biology of Heparin, editors: R. L. Lundblad et al, Elsevier North Holland, N.Y., pps. 435-447, 1981. According to some researchers, heparin produces a state of "platelet activation" W. D. Comper, Heparin, Gordon and Breach Science Publishers, New York, Chapter 7, "Extracellular Interactions," pps. 175-248, 1981, which causes platelets to aggregate or clump. In addition, activated platelets tend to degranulate thereby releasing substances including ADP, PF4, etc.; this has been called a "platelet release reaction." F. Fabris, et al, "The Effect of Heparins on Platelet Release Reaction," Heparin, New Biochemical and Medical Aspects, editors: I. Witt, Walter de Gruyter & Company, Berlin, pps. 207-225, 1982.
It has also been observed that platelets, once activated, notwithstanding disaggregating, suffer from impaired response to stimuli. See, e.g., S. N. Harris, et al, "Evaluation of Platelet Function During Autologous Function During Autologous Blood Donation," Anesthesiology 75:A1121, 1991. Thus, it is a limitation of the prior art that post-heparinization rapid blood sequestration procedures is inherently unsafe because of heparin's noxious affect upon platelets and the risk of hemodynamic instability. Other likely adverse affects upon platelets include heparin-induced transient or reversible thrombocytopenia, and heparin induced thrombocytopenia (HIT). While the incidence of these thrombocytopenia conditions are rare, the vulnerabilities associated with the use of heparin to promote rapid blood sequestration should be evident to those familiar with the art.
Another methodology for removing blood from a patient intraoperatively with the simultaneous administration of crystalloid or colloid to maintain normovolemia is acute normovolemic hemodilution. This technique is described by L. Sterling and H. L. Zauder in the article "Acute Normovolemic Hemodilution" published in Transfusion, vol. 31, pp 857-868, in 1991. A suitable volume of blood is collected into blood bags containing anticoagulant and stored for use during subsequent surgery. Generally, acute normovolemic hemodilution tends to reduce the amount of allogeneic blood used during a surgical procedure. Unfortunately, if such collected blood is not used within 6 hours of removal from a patient, A.A.B.B. rules stipulate that the collected blood must be refrigerated to minimize infection risks. See, 21 C.F.R. .sctn. 640.2.
As will be appreciated by practitioners in the art, the theoretical basis for the acute normovolemic hemodilution methodology is that it is advantageous to lose blood with a lower Hb/Hematocrit (Hct) than a higher Hb/Hct. For instance, if a patient with a Hct of 0.45 loses 1 liter of whole blood during a surgical procedure, then 450 ml of red blood cells have been lost. If, however, after acute normovolemic hemodilution has been performed, the Hct is reduced to 0.25, then only 250 ml of red blood cells have been lost. Simultaneously with acute normovolemic hemodilution, arterial oxygen content decreases, cardiac output increases as much as 36%, tissue extraction increases, and blood viscosity decreases. Since coronary blood flow is proportional to cardiac output, coronary blood flow increases concomitantly with increased cardiac output.
There is also evidence that these physiologic responses to acute normovolemic hemodilution may compromise patient safety by producing wall motion abnormalities and myocardial ischemica. See, e.g., the paper by J. Gillon published in Transfusion, vol. 34, pp. 269-271, 1994. But there are studies that indicate that patients may tolerate large amounts of intraoperative hemodilution. See, e.g., two papers published in Anesth Analg: by Fontana, et al., in vol. 80, pp. 219-225, 1995 and by Van Woerkens, et al., in vol. 75, pp. 818-821, 1992. Those skilled in the art have developed various formulas for calculating acute normovolemic hemodilution end-points and for calculating the Hb of collected blood.
It is also known in the transfusion art that there are religious objections to use of allogeneic blood. Jehovah's Witnesses refuse the administration of all allogeneic blood products. Accordingly, autologous predonation is incompatible with the beliefs of Jehovah's Witnesses: since blood leaves a patient's body for prolonged periods of time before being used, predonation violates the sacred principle that blood must not be consumed or that there must be abstinence from blood. It should be noted, however, that the extra corporeal circulation provided by a heart-lung apparatus during cardiac surgery is acceptable to Jehovah's Witnesses because a patient's blood is diverted via cannulae to an oxygenator and then pumped back to the patient via another set of cannulae. Thus, this extra corporeal circulation functions as an extension of a patient's circulatory system, sustaining continuous connection therewith. That is, a patient's blood circulates through a closed circuit integral with the patient's own circulatory system.
While autotransfusion and intraoperative blood salvage methodologies generally function as extensions of a patient's circulatory system, blood exiting from a surgical wound would appear to be divorced from the closed circuit. By adapting current autotransfusion devices and connecting such devices prior to surgery, blood that is aspirated or suctioned from a surgical wound is kept within the closed circuit.
Similarly, during acute normovolemic hemodilution, if there is an interruption in the circulation of blood, wherein blood is temporarily collected into blood bags, then the closed circuit aspect is destroyed. To be compatible with the beliefs of Jehovah's Witnesses, there must at least be a constant, albeit slow, trickle of blood throughout the extended circulatory system.
There have been improvements in the art to enable safer and less objectionable transfusion methodologies during surgical procedures. For instance, in U.S. Pat. Nos. 4,047,526 and 4,006,745, Reynolds et al. and Sorenson et al. teach autologous blood systems that first suck blood from the surgical field and then filter and return this blood to the patient. As will be appreciated by those skilled in the art, these autologous techniques cannot be administered in the presence of infection because of likely contamination of the patient's blood. An additional disadvantage of the methods disclosed by Reynolds and Sorenson is that no consideration is made of the possibility that various components of a patient's blood may be damaged by the suction process nor how coagulation aspects and platelets may be activated or consumed, while being aspirated from a surgical field.
Sharp, in U.S. Pat. No. 4,838,861 teaches blood preservation by ultrahemodilution wherein a patient's blood is withdrawn, diluted and then processed prior to be returned to the patient. But Sharp does not contemplate a closed circuit wherein a patient's circulation is uninterrupted. Similarly, in U.S. Pat. No. 5,078,677, Gentelia et al. teach an apparatus for postoperatively collecting a patient's blood and then for the reinfusion of this blood into the patient. Continuity with the patient's circulatory system appears to be interrupted when the reinfusion apparatus is disconnected from the patient's chest drainage section.
Roth et al. disclose synthetic oxygen carriers in the context of acute normovolemic hemodilution in U.S. Pat. No. 5,344,393. More particularly, Roth's perflubron carriers are intended to be injected into a patient for augmenting the amount of oxygen carried in the bloodstream; in so doing, these carriers are described as assisting normovolemic hemodilution and predonation. It appears that a benefit of these synthetic oxygen carriers is that end-points of blood sequestration could be greater than currently considered practicable. Hence, under proper conditions, patients may be able to tolerate greater volumes of sequestered blood since oxygen would be delivered not only by the red blood cells, but also by a perflubron emulsion as contemplated by Roth.
U.S. Pat. Nos. 5,074,838; 5,368,555; 5,318,511; and 4,623,518, are indicative of the art of extra corporeal circulation of the blood.
Notwithstanding these and related developments in the art, there appears to be no apparatus nor methodology which provides sufficiently safe and reliable conditions for autologous blood sequestration. Sequestration of blood prior to onset of a surgical procedure affords the most practicable methodology for reducing dependency upon allogeneic blood products. A methodology is needed wherein packed red blood cells and various coagulation factors may safely be removed from patients and then be recycled to the patient after surgery is completed. A practical, portable system that enables such effective application of acute normovolemic hemodilution is unknown in the art.
Furthermore, there is neither apparatus nor methodology that affords the advantage associated with keeping sequestered blood at 37.degree. C. As will be understood by those skilled in the art, keeping blood substantially at this temperature optimizes the performance of platelets for clotting functions and the performance of leukocytes for mopping up bacteria contained in sequestered blood.
It is a disadvantage of the art that an anesthesiologist typically must contact a local blood bank to have specially constructed blood bags delivered to hospital operating rooms and the like, prior to surgical procedures. Commonly used sequestration procedures are slow and tedious, in which sequestered blood is maintained at room temperature, unfortunately, significantly below body temperature of 37.degree. C. It will be appreciated by those skilled in the art that the introduction of 4 units of blood at room temperature into a patient's circulatory system could significantly reduce the patient's body temperature. This tendency is particularly germane in pediatric patients wherein heat loss occurs rapidly in the operating room environment, and, indeed, is associated with increased morbidity.
Furthermore, if blood products are not administered within 6 hours of being obtained, under A.A.B.B. rules, the blood must be refrigerated. But, the administration of cold packed red blood cells to pediatric patients has been associated with life-threatening arrhythmias. While blood warmers are, of course, available, they demand special apparatus and concomitant tubing, and, unfortunately, increase health care costs.
Thus, it is clear that there is presently no sequestration procedure which is inherently compatible with a patient's circulatory system with regard to blood flow and temperature, and which reliably forms a closed circuit therewith. Thus, it would be advantageous to utilize an apparatus which enables autologous blood sequestration via a closed circuit thereby assuring no interruption of a patient's innate circulatory system. Accordingly, these limitations and disadvantages of the prior art are overcome with the present invention, and improved means and techniques are provided which are useful for effectively and reliably sequestering a patient's own blood in a closed circuit arrangement that sustains the flow and temperature throughout the patient's circulatory system.